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Peroxisomal proliferator-activated receptor-alpha-dependent inhibition of endothelial cell proliferation and

Ambra Pozzi1, Maria Raquel Ibanez, Arnaldo E Gatica

  • 1Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.

The Journal of Biological Chemistry
|April 5, 2007
PubMed

Insights

Peroxisomal proliferator-activated nuclear receptor-alpha (PPARalpha) activation significantly reduced tumor growth and vascularization by decreasing pro-angiogenic metabolites. These anti-tumorigenic effects are PPARalpha-dependent and suggest potential cancer therapies.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Pharmacology

Background:

  • Peroxisomal proliferator-activated nuclear receptor-alpha (PPARalpha) regulates lipid metabolism, energy homeostasis, and inflammatory responses.
  • PPARalpha influences cell proliferation and modulates the expression of Cyp4a and Cyp2c genes.
  • PPARalpha ligands are targets for hypolipidemic drugs, with emerging roles in other biological processes.

Purpose of the Study:

  • To investigate the role of PPARalpha and its target gene Cyp2c in tumorigenesis.
  • To evaluate the anti-tumorigenic and anti-angiogenic effects of a PPARalpha-selective ligand, Wy-14,643.
  • To determine the involvement of PPARalpha-mediated pathways in tumor growth and vascularization.

Main Methods:

  • Treatment of tumor-bearing mice with Wy-14,643, a PPARalpha agonist.
  • Assessment of tumor growth, vascularization, and plasma levels of epoxygenase metabolites (EETs).
  • Analysis of hepatic Cyp2c epoxygenase expression and endothelial cell proliferation in vitro.

Main Results:

  • Wy-14,643 treatment markedly reduced tumor growth and vascularization in wild-type mice.
  • Reduced plasma EET levels, hepatic EET biosynthesis, and Cyp2c expression were observed post-treatment.
  • PPARalpha knockout mice showed no reduction in tumor growth, confirming PPARalpha mediation.
  • Wy-14,643 inhibited endothelial cell proliferation and capillary-like structure formation, effects reversed by EETs.

Conclusions:

  • PPARalpha activation exhibits significant anti-angiogenic and anti-tumorigenic properties.
  • The Cyp2c epoxygenase gene is a key target mediating PPARalpha's anti-cancer effects.
  • PPARalpha and its ligands represent potential therapeutic agents for cancer treatment.

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